Submissions for variant NM_001242882.2(NAXD):c.54_57del (p.Ala20fs)

dbSNP: rs773887880

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000755012	SCV002053753	pathogenic	NAD(P)HX dehydratase deficiency		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855857	SCV002123001	pathogenic	not provided	2023-07-07	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individuals with clinical features of progressive encephalopathy with brain edema and leukoencephalopathy (PMID: 30576410, 32462209). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NAXD gene expression (PMID: 32462209). ClinVar contains an entry for this variant (Variation ID: 617759). This variant is also known as c.51_54delAGAA (p.Ala20Phefs*9). This variant is present in population databases (rs773887880, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ala38Phefs*9) in the NAXD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAXD are known to be pathogenic (PMID: 30576410, 32462209).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000755012	SCV002769388	pathogenic	NAD(P)HX dehydratase deficiency	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 10). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (PMID: 31755961, 32462209). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with neurodegenerative disorder exacerbated by febrile illnesses. (ClinVar, PMID: 30576410, 32462209). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired localisation of protein (PMID: 32462209). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000755012	SCV004047087	pathogenic	NAD(P)HX dehydratase deficiency		criteria provided, single submitter	clinical testing	The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This variant is reported with the allele frequency (0.004%) in the gnomAD and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001855857	SCV005080461	pathogenic	not provided	2023-09-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a loss of protein expression (Borna et al., 2020); This variant is associated with the following publications: (PMID: 32462209, 30576410)
OMIM	RCV000755012	SCV000882836	pathogenic	NAD(P)HX dehydratase deficiency	2020-09-16	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003965558	SCV004780230	pathogenic	NAXD-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) deficiency (reported as c.54_57delAAGA using another transcript in Van Bergen et al. 2019. PubMed ID: 30576410). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NAXD are expected to be pathogenic. This variant is interpreted as pathogenic.